Long-Term Treatment
Treatment with anti-epileptic drugs (AEDs) is usually initiated or strongly considered after a first seizure for the following patients:
- Children and adults who have had two or three seizures, unless there is either a long separation between seizures or the seizure is provoked by an injury or other specific causes. (In children, risk for recurrence after a single unprovoked seizure is rare. The risk even after a second seizure is low, even when the seizure is prolonged.)
- Children and adults after a single seizure if tests reveal any brain injury or if specific syndromes put a person at special risk for recurrence, for instance, in cases of myoclonic epilepsy.
There is some debate about whether to treat every adult patient with an AED after a single initial seizure. Some experts do not recommend treating adult patients after a single seizure if they have a normal neurologic examination, EEG, and imaging studies. Such patients should also agree to accept the risk of a subsequent seizure.
Some physicians believe, however, that any adult who has a first seizure should begin ongoing AED treatment, since 30% to 70% of these patients are likely to experience a subsequent event. Furthermore, according to one study, when young adults were given a single drug (usually carbamazepine) after a first generalized seizure, only 22% had a subsequent seizure compared to about 70% of those who were not given treatment.
Determining an Anti-Epileptic Drug (AED) Regimen
Most epileptic seizures can be controlled using a single-drug regimen. The first-line AED drugs include phenytoin (Dilantin), carbamazepine (Tegretol, Carbatrol), and divalproex sodium (Depakote). There are nine other anti-epileptic agents that have become available since 1993. Patients generally begin with low doses and build up until the seizures are controlled or a toxic reaction occurs. If a single agent fails to control seizures, then other agents are added on. The specific drugs and whether more than one should be used are determined by various factors, including the patient's age and the seizure's type, frequency, and cause.
Treatment Success and Failure of AEDs
In one 2000 study that followed over 500 patients for three to five years, 63% of patients treated with AEDs become seizure-free during that period. In the same study, drugs failed to control epilepsy in about 30% of patients. Those with the poorest chances of success were those who started AED treatment after more than 20 seizures and those who failed to exhibit any benefit from their initial drug regimen. (In the latter case, subsequent drugs worked in only 11% of patients.)
Reasons for Failure. An AED's failure to reduce seizures can be attributed to factors such as:
- The wrong dose level.
- Improper timing.
- Introducing the medication too rapidly.
- Not managing conditions that triggered the seizure.
- Instability of the drugs. Many of the tablet forms disintegrate easily with moisture, so pills should be stored in a dry place, not in the bathroom, and kept away from heat.
- Toxicity. Some research indicates that over 40% of patients experience toxic effects from older AEDs, which often causes them to withdraw. Among the most distressing are sleepiness, problems in coordination, and weight gain.
- Some evidence suggests that about a quarter of patients who do not respond to AEDs actually have nonepileptic seizures that in many cases are caused by psychiatric conditions (e.g., panic attack, personality disorders).
The physician should first address these issues. If the patient still does not respond, the doctor will usually try a different drug. If this fails, one or even two additional drugs at a time may be used. It should be noted that, while many drugs are now available for epilepsy, if seizures do not respond to the first two or three, the odds of a fourth or fifth working diminish greatly. In such cases, the patient should ask about surgical alternatives.
Noncompliance. This is a serious problem, particularly in young people. It is extremely important to take medication as prescribed by the physician, since studies have shown that uncontrolled epileptic attacks lead to changes in the neurons that may cause intractable epilepsy. In young people, positive attitude, continued support from family and health care providers, emotional well-being, and good treatment results are among the factors that can increase patient compliance. Conversely, unhealthful behaviors, such as smoking and alcohol use, can have a negative effect.
Monitoring Effects
During the first few months of therapy, the physician will probably monitor drug levels in the blood once or twice in order to adjust dosages. Monitoring is used to check for AED complications, and to be sure the patient is complying with the regimen. Many experts feel, however, that these blood tests are a less reliable indicator of problems than the patient's own self-observations of his or her responses to the drug. For instance, blood tests may suggest that the dosage levels are insufficient according to general standards, yet the individual patient may be seizure-free and leading a normal life.
General Information on Side Effects of AEDs
All anti-epileptic drugs have side effects, which vary depending on the drug. Increasingly, however, AEDs are being designed to specifically target mechanisms causing seizures and should have fewer widespread effects. The complexity and potential severity of side effects are amplified when more than one drug is used. Seizures themselves can be a side effect of AEDs.
Some problems common to many of the AEDs include the following:
- Fatigue and sleepiness.
- Changes in appetite and weight.
- Loss of coordination.
- Gastrointestinal problems.
- Possible bone loss leading to osteoporosis, including in young people. The older agents, such as phenytoin, phenobarbital, carbamazepine, and primidone, have more severe effects than valproic acid and the newer agents. Many of the latter agents, however, also pose some risk. Patients ask their physicians about taking calcium and vitamin D supplements, a bone-protecting exercise regimen, and being monitored with bone densitrometry.
- Changes in skin and hair, including acne from phenytoin, excessive hair growth from phenytoin and carbamazepine, and hair loss from valproate.
- Reproductive problems.
- Severe allergic reactions (particularly from particularly phenytoin, carbamazepine, phenobarbital, and primidone). They can include severe skin rashes, fever, and occasionally even inflammation or swelling of the liver, kidneys, or lymph nodes.
Drug Interactions
AEDs interact with many other drugs, making them more or less potent, so it is very important that patients inform their physician of everything they are taking, including over-the-counter medications and vitamins. Some specific interactions are covered later in discussions of individual agents. Many of the AEDs have some common effects on other medications; several reduce the effectiveness of oral contraception, for example. Erythromycin and some drugs used to treat asthma, ulcers, and heart disease can interact with AEDs.
Discontinuing Drug Therapy
An estimated 60% of all patients treated effectively can stop taking AEDs within five to 10 years. Evidence in 2002 suggests that medications in children should not be halted for at least two years after the last seizure, particularly if they have partial seizures and abnormal EEGs. It is not clear whether children who have been free of generalized seizures need to wait more than two years or if they can withdraw earlier. There is also no clear evidence on whether adults who are free of any seizure type can safely withdraw from their medications within two years of their last seizure of if they should wait.
In any case, attempts to halt drugs should be done during periods when seizures will cause the least harm. For instance, the best time to test the effects of drug withdrawal in teenagers might be about a year before they are eligible to drive.
Indications for Surgery
Surgery is an excellent option for appropriate patients who do not respond to medications and have epilepsy in the temporal lobe (where most complex partial seizures occur). Younger people are preferred candidates for surgery because older people have more difficulty with rehabilitation.
In general, about 75% of appropriate patients can expect at least partial remission at experienced centers, with some centers reporting even better results. Temporal lobe surgery may even improve quality of life, prolong survival, and help prevent sudden deaths associated with epilepsy. Yet despite these benefits and the significant chance for failure after trying four or five drugs, physicians now wait an average of 15 to 19 years before they consider a surgical alternative.
Treatment for Special Population Groups
Treatment of Specific Seizure Syndromes in Infants and Small Children.
- Lennox-Gastaut. The newer drugs, felbamate, lamotrigine, and topiramate, are useful in treating this syndrome in children two years and older. (Note: serious rash is more common in young children with lamotrigine than it is in adults.)
- Infantile spasms. Infantile spasms are treated with vigabatrin, adrenocorticotropic hormone (ACTH), or valproate. Some experts recommend that vigabatrin be given first and ACTH administered 10 to 14 days later. In one small study, no infants who were given this combination relapsed after four months. Newer drugs may also be effective for this problem but their effects on small children are not yet wholly known.
- Acute tonic-clonic convulsions and convulsive status epilepticus. Intravenous diazepam, a drug known as a benzodiazepine, is the first choice. Rectal administration of benzodiazepines, either diazepam or lorazepam, may also be beneficial. Some evidence suggests that rectal administration of lorazepam is safer and more effective than diazepam, but more research is needed.
- Prolonged febrile seizures. Prolonged febrile seizures in infants and small children may be treated with intravenous benzodiazepines, usually diazepam. Other agents under investigation include nasally administered midazolam (a newer benzodiazepine). In one study, it was effective for managing febrile seizures in children. It is absorbed quickly and is as safe as diazepam. With the proper instruction, it can also be administered by caregivers at home.
Treatment of the Elderly. Anti-epileptic drugs interact with many other agents and may cause special problems in older patients who use multiple medications for other health problems. Elderly patients should have liver and kidney function tests performed before starting antiseizure medication. Standard drugs are usually effective, while safe, newer ones (including gabapentin, lamotrigine, oxcarbazepine and gamma-vinyl-GABA) may sometimes prove to be useful as sole therapy. These newer drugs also increase patient compliance, in that they have fewer side effects than the older ones.
Treatment of Women. Hormonal fluctuations affect epilepsy in about a third to a half of female patients. Estrogen appears to increase activity and progesterone reduces it. The effect of pregnancy on women with epilepsy is complex. The following treatments may help or affect women with epilepsy:
- Hormonal Agents that Suppress Ovulation. When seizures in women are worsened by hormonal changes, such as during the menstrual cycle, suppressing ovulation may be recommended using drugs called gonadotropin-releasing hormone agonists.
- Hysterectomy. Women with epilepsy who no longer wish to bear children may consider hysterectomy (surgical removal of the uterus) or oophorectomy (surgical removal of the ovaries). Each of these treatments must be accompanied by estrogen replacement therapy.
- Oral contraceptives. Antiseizure medications affect many oral contraceptives (OCs). Carbamazepine, phenytoin, phenobarbital, primidone, oxcarbazepine, and topiramate reduce the effects of OCs. Valproate does not, and may even increase hormonal levels. Gabapentin, lamotrigine, tiagabine, and vigabatrin may also prove to be safe with OCs, but more research is needed. The best contraceptive agents for women with epilepsy at time may be progestins. Injected progestins may actually help prevent seizures in some cases.
Effects of Epilepsy on Female Fertility and Pregnancy
Studies have been conflicting on the effects of fertility from epilepsy, but most suggest that fertility rates among women with epilepsy are lower than among women in the general population. A number factors, including anti-epileptic drugs (AEDs) or social factors, such as marriage at an older age, may contribute to this lower rate. Certain AEDs, particularly valproate, disrupt ovulation and menstruation by increasing male hormone levels and weight and causing polycystic ovaries.
Effects of Epilepsy on the Pregnant Patient and the Fetus
In women who become pregnant, there is a risk for uncontrolled seizures and birth defects from antiseizure medications. In studies of women who were carefully monitored, however, 95% of pregnancies (which is close to normal) had favorable outcomes.
Effects of Seizures. Isolated seizures do not appear to pose any adverse effects to the mother or the unborn child, but repeated seizures and status epilepticus can lead to great dangers. In one study, the effect of epilepsy on complications during pregnancy was the same as in non-epileptic women except for a higher rate of premature deliveries (8.2% in the women with epilepsy).
Effects of Medications on the Fetus. All standard antiseizure drugs pose a significant risk for birth defects, which include malformations of the face and hands or more serious effects on the heart or mental development. The more medications required the higher the risk. (Epilepsy itself, however, does not appear to pose any higher risk for birth defects in the child.) Pregnant women who need to continue medication should be on the lowest possible dose of a single type of drug, if feasible.
Effect of Pregnancy on Seizure Frequency
The frequency and intensity of seizures vary widely in women with epilepsy. About 25% of pregnant women with epilepsy face an increase in events, and the risk is highest in those who have more than one seizure per month prior to becoming pregnant. In most cases, however, there is no change at all. Some pregnant women even have a decrease in seizures. The risk is lower in women who experience less than one seizure in the nine months prior to becoming pregnant. The following conditions may contribute to an increase in seizures during pregnancy:
- Nausea and vomiting. (Vitamin B6 and antihistamines may help with nausea.)
- Fluid retention.
- Higher estrogen levels.
- Psychological and emotional stress.
- Medication noncompliance from fear of side effects.
- Problems with sleeping.
- Changes in absorption of anticonvulsants.
Steps for Women Who Want to Become Pregnant
- A woman who wishes to become pregnant and has been seizure-free for two or more years may attempt to discontinue drugs under her physicians supervision.
- If she has not been seizure-free, she should continue medications but try to reduce them to a single agent, if possible. (Again under a physicians supervision.)
Steps During Unplanned Pregnancy
- If a woman taking antiseizure medications has an unplanned pregnancy, there may be no point in switching medications right away, since the effects of the drugs last for 10 weeks. However, she should notify her physician immediately.
- She should be carefully monitored for both drug levels and any abnormalities in the fetus. Ideally, drug levels should be measured every one or two months or more often if seizures are not controlled. Dosage levels should be adjusted accordingly.
- She should also be carefully monitored with ultrasonic evaluation and amniocentesis (visual tests and examination of the fluid in the womb for birth defects and other fetal problems).
Drugs Used During Pregnancy
It is very difficult to determine which drugs are safest for pregnant women because researchers (and patients) do not want to take chances deliberately testing unknown agents on unborn children. In one 2003 study, the risk for birth defects was significant with valproate, carbamazepine, and oxcarbazepine. Few studies exist on this difficult problem, however, and no AED has an established safety record during pregnancy.
The risk for malformation is higher when more medications are used. For example, there is a 3% risk of birth defects with women who use one anticonvulsant; this risk increases to 20% when four drugs are used. Birth defects are more likely to occur when drugs are administered within the first trimester of pregnancy. The pregnant woman should use the most effective anticonvulsant medication for her type of epilepsy at the lowest dose possible to control seizures.
Birth Defects Associated with Medication. The most common birth defects related to anticonvulsant drugs are:
- Cleft lip or palate (risk from phenobarbital, phenytoin, valproate).
- Genital or urinary abnormalities (risk from most standard agents).
- Neural tube defects (NTD) in the skull or spinal column (risk of 2% with valproate and 1% with carbamazepine). These complications are most often due to lower folic acid levels caused by both pregnancy itself and antiseizure drugs. Supplements can help prevent this problem. Folic acid is recommended for all pregnant women, in any case, and those with epilepsy should talk with their physician about taking a supplement of folic acid (5 mg) at least three months before conception, if possible, as well as during the first trimester.
- Mental impairment (known risk with phenytoin and valproate; inconclusive in carbamazepine and phenobarbital).
- Heart defects (risk from phenobarbital, phenytoin, valproate).
- Many of the major antiseizure drugs also cause a deficiency in vitamin K clotting factors that increases the risk for hemorrhage in the newborn. Treatment with vitamin K during the last month and a single dose given to the newborn is recommended.
Labor and Delivery
Seizures occur during labor and after delivery in a small percentage of women with epilepsy. The following labor complications are more common among pregnant women with epilepsy: vaginal bleeding, anemia, and preeclampsia (acutely elevated blood pressure in the third trimester). If seizures occur during labor, they are generally treated intravenously with benzodiazepines or phenytoin. If tonic-clonic seizures, absence seizures, or status epilepticus occur, a cesarean section may be appropriate.
Postnatal Care
Monitoring the Infant. The infant should be thoroughly examined for any malformations. Also, if the mother was given phenobarbital or primidone while pregnant, the infant should be monitored for up to eight months to see if withdrawal symptoms develop. Drug dosages will also need to be adjusted for the mother after delivery.
Breastfeeding. Women on most AEDs can usually nurse their babies, since usually only a small amount of the drug enters the breast milk. The lowest levels are with phenytoin and valproate. (Ethosuximide and possibly levetiracetam are exceptions and should be avoided when a woman is breastfeeding. Women taking phenobarbital are also usually advised not to nurse.) A mother should watch for signs of lethargy or extreme sleepiness in her infant, which could be caused by her medication.
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